Valve for osmotic devices

ABSTRACT

An osmotic delivery system for controlled delivery of a beneficial agent includes an implant capsule having a beneficial agent reservoir, an osmotic agent which expands on contact with fluid imbibed through a permeable membrane retained by the implant capsule, a delivery port, and a valve for opening and closing the delivery port. When the osmotic agent expands, a pressure is exerted against a separating member positioned between the beneficial agent reservoir and the osmotic agent. The separating member moves within the capsule, thereby forcing the valve to move a distance such that the beneficial agent can exit the reservoir through the delivery port.

[0001] This application claims priority based on U.S. Provisional PatentApplication Serial No. 60/171,305, filed Dec. 21, 1999, which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to osmotic delivery devices for deliveringbeneficial agents, and more particularly, to osmotic delivery deviceshaving an osmotic engine and a valve to prevent expulsion of thebeneficial agents.

[0004] 2. Description of the Related Art

[0005] Controlled delivery of beneficial agents, such as drugs, in themedical and veterinary fields has been accomplished by a variety ofmethods. One method for controlled prolonged delivery of beneficialagents involves the use of osmotic delivery systems. These systems canbe implanted within a body of a human or animal to release beneficialagents in a controlled manner over a preselected time or administrationperiod. In general, osmotic delivery systems operate by imbibing liquidfrom the outside environment and releasing corresponding amounts of thebeneficial agent.

[0006] A known osmotic delivery system, commonly referred to as an“osmotic pump,” generally includes some type of a capsule or enclosurehaving a semipermeable portion which selectively passes water into aninterior of the capsule containing a water-attracting osmotic agent. Inone known osmotic delivery system the walls of the capsule aresubstantially impermeable to items within and outside the capsule. Amembrane plug is inserted into one end of the capsule and acts as thesemipermeable portion allowing water to pass into the interior of thecapsule. The difference in osmolarity between the water-attractingosmotic agent and the environment surrounding the capsule causes waterto pass through the membrane plug into the capsule which in turn causesthe beneficial agent within the capsule to be delivered through adelivery orifice. The water-attracting osmotic agent may be thebeneficial agent delivered to the patient; however, in most cases aseparate osmotic agent is used specifically for its ability to drawwater into the capsule.

[0007] When a separate osmotic agent is used, the osmotic agent may beseparated from the beneficial agent within the capsule by a movabledividing member or piston. The structure of the capsule is such that thecapsule does not expand when the osmotic agent takes in water andexpands. As the osmotic agent expands, it causes the piston to move andthe beneficial agent to be discharged through the delivery orifice atthe same rate as the liquid, which is typically water, enters theosmotic agent by osmosis. Osmotic delivery systems may be designed todeliver a beneficial agent at a controlled constant rate, a varyingrate, or in a pulsatile manner.

[0008] In the known osmotic delivery systems, an osmotic tablet isgenerally used as the osmotic agent and is placed inside the capsuleadjacent the piston. A membrane plug is placed in an opening in thecapsule through which the tablet and piston were inserted. Knownmembrane plugs are typically cylindrical members which seal the interiorof the capsule from the exterior environment, permitting only certainliquid molecules from the environment of use to permeate through themembrane plug into the interior of the capsule. The rate that the liquidpermeates through the membrane plug controls the rate at which theosmotic agent expands and drives the beneficial agent from the deliverysystem through the delivery orifice. The rate of delivery of thebeneficial agent from the osmotic delivery system may be controlled byvarying the size of the beneficial agent delivery orifice, the osmoticmaterial, a size and shape of the membrane plug, or the permeabilitycoefficient of the membrane plug.

[0009] It is desirable to seal the beneficial agent delivery orifice ofthe delivery system to prevent incursion of materials into the deliverysystem before sufficient osmotic pressure exists to insure a flow of thebeneficial agent through the orifice. Protecting the beneficial agentfrom the external environment is particularly important when thebeneficial agent is a protein formulation or other agent which breaksdown when in contact with certain environmental compositions.

[0010] In order to prevent contamination or early release of thebeneficial agent, some delivery systems are provided with a plug in theorifice which is discharged upon movement of the piston by the fluidpressure within the system. Typically, such osmotic delivery systems usemechanical plugs, bioeroding, or dissolving plugs.

[0011] With mechanical plugs, such plugs are chemically stable materialsdischarged from the delivery system on movement of a piston containedwithin the system. Premature release of the beneficial agent may occurwhen the delivery system is jarred, thereby loosening the mechanicalplug from the system. Further, mechanical plugs expelled from thedelivery device may not be acceptable with the patient when left in thepatient's body at the implant site.

[0012] Bio-eroding or dissolving plugs also present drug deliveryproblems since such plugs allow the drug delivery orifice to openregardless of whether or not the osmotic agent can exert sufficienthydraulic pressure to insure flow of the beneficial agent.

[0013] Because of the above-identified problems associated with currentosmotic delivery systems, it is desirable to prevent contamination ofthe beneficial agent and to prevent beneficial agent leakage byproviding a delivery orifice valve which is not expelled into thepatient's body.

SUMMARY OF THE INVENTION

[0014] The present invention relates to osmotic delivery systems havingan osmotic engine and a valve to prevent contamination and/or expulsionof the beneficial agents.

[0015] In accordance with one aspect of the present invention, adelivery system for controlled delivery of a beneficial agent includesan implantable capsule having a delivery orifice, a separating memberdividing the capsule into a beneficial agent reservoir and a drivingreservoir, an osmotic engine in the driving reservoir, and a valvemember that can move from a closed position to an open position. In theclosed position, the valve member prevents the expulsion of beneficialagent from the beneficial agent reservoir through the delivery orifice.The implantable capsule can include an attachable cap having a vent. Inoperation, the osmotic engine imbibes fluid thereby causing the engineto swell. This swelling causes the osmotic engine to exert a pressure onthe separating member whereby such pressure moves the separating member,the beneficial agent reservoir, and the valve member a distance suchthat the valve member moves to an open position, allowing passage ofbeneficial agent through the delivery orifice at a desired deliveryrate.

[0016] In accordance with another aspect of the present invention, amethod of preventing contamination from entering the osmotic deliverydevice before activation includes the steps of providing a deliverydevice capsule enclosing a first chamber which contains a beneficialagent and a valve member. The first chamber has an opening communicatingwith the external environment. Before activation of the delivery device,the valve member occludes the opening. This occlusion prevents thebeneficial agent from leaving the device, as well as prevents theincursion of contaminants into the device.

[0017] In accordance with an additional aspect of the present invention,a method of controlling an initial release of a beneficial agent from anosmotic delivery device includes the steps of providing a deliverydevice capsule which encloses a first chamber containing the beneficialagent, a valve member, and a second chamber containing an osmotic agent.The first chamber has a beneficial agent delivery orifice communicatingwith the external environment. The valve member is initially in a closedposition and blocks beneficial agent from passing through the beneficialagent delivery orifice. Upon implantation, the osmotic agent imbibessurrounding fluid to form an osmotic solute which expands and exerts apressure on the first chamber. The osmotic imbibition of surroundingfluid builds pressure within the osmotic engine until sufficient forceis exerted to move the first chamber and valve member, the valve membermoving from the closed position to an open position. With the valve inthe opened position, beneficial agent contained in the first chamber canpass through the beneficial agent delivery orifice to the externalenvironment.

[0018] The present invention provides the advantage of a morecontrollable beneficial agent delivery rate by preventing expulsion ofbeneficial agent from the drug reservoir by using a valve to occlude thedrug delivery orifice. The valve does not allow beneficial agent to passthrough the delivery orifice until sufficient hydraulic pressure existsto displace the beneficial agent from the drug reservoir. Moreover, thepresent invention retains the valve within delivery device, wherebyremoving the implant from the patient after delivering the medicationallows retrieval of both the valve and the implant device.

BRIEF DESCRIPTION OF THE FIGURES

[0019] The invention will now be described in greater detail withreference to the preferred embodiments illustrated in the accompanyingdrawings, in which like elements bear like reference numerals, andwherein:

[0020]FIG. 1 is a side cross-sectional view of an osmotic deliverydevice according to the present invention;

[0021]FIG. 2 is a side cross-sectional view of the osmotic deliverydevice of FIG. 1 delivering a beneficial agent through an orifice;

[0022]FIG. 3 is a side cross-sectional view of an osmotic deliverysystem having an alternative embodiment of a cap with the cap in closedposition; and

[0023]FIG. 4 is a side cross-sectional view of an osmotic deliverysystem having an alternative embodiment of a cap with the cap in openedposition.

DETAILED DESCRIPTION

[0024] The present invention relates to an osmotic delivery system forcontrolled delivery of a beneficial agent. FIGS. 1-4 illustrate twoexamples of osmotic delivery devices 10 according to the presentinvention.

[0025] The osmotic drug delivery device 10, as illustrated in FIG. 1,includes a movable valve 28, a first chamber 22 containing a beneficialagent, a separating member 20, and a second chamber 24 containing anosmotic engine or agent, all of which are enclosed within an elongatedsubstantially cylindrical enclosure or capsule 12. The capsule 12 has afirst end 14 and an open end 16. The first end 14 of the capsule 12 hasone or more orifices or ports 18 for delivering a beneficial agentcontained within a first chamber 22 of the osmotic delivery device 10 toan external environment. In most configurations, one delivery port 18will suffice. However, two or more delivery ports 18 may be presentwithout departing from the present invention.

[0026] The valve 28 occludes the delivery orifice 18 when the valve isin a closed position, preventing the beneficial agent in the firstchamber 22 from leaving the delivery device 10 as well as preventing theincursion of foreign materials into the device. The dimensions of thevalve 28 in terms of both diameter and length are selected such that thevalve will not exit the delivery device 10 through the delivery orifice18.

[0027] The separating member 20 also separates the first chamber 22containing the beneficial agent from the second chamber 24 containingthe osmotic agent. The separating member 20 and valve 28 aresubstantially cylindrical members which are configured to fit within thecapsule 12 and are slidably movable along a longitudinal directionwithin the capsule. The separating member and valve 20, 28 preferablyare formed of a resilient material which is impermeable to thecompositions within the capsule 12, and at least a portion of theseparating member 20 and the valve 28 forms a seal with the innersurface of said capsule 12.

[0028] In addition, the movable separating member and valve 20, 28 maybe flexible members such as pistons, partitions, pads, flat sheets,spheroids, or rigid metal alloys, and may be made of any number of inertmaterials. Furthermore, the osmotic device 10 may function without thepiston 20, having simply an interface between the osmotic agent and thebeneficial agent.

[0029] A semipermeable membrane 30 couples with the capsule 12 at theopen end 16 and encloses the second chamber 24 containing the osmoticagent. The osmotic agent may be, for example, a nonvolatile watersoluble osmagent, an osmopolymer which swells on contact with water, ora mixture of the two. The elongated capsule 12 is formed of a materialwhich is sufficiently rigid to withstand expansion of the osmotic agentcontained within a second chamber 24 of the delivery device 10 withoutchanging size or shape. The elongated capsule 12 is preferablysubstantially impermeable to fluids in the environment as well as toingredients contained within the osmotic delivery device 10 such thatthe migration of such materials into or out of the device through theimpermeable material of the capsule is so low as to have substantiallyno adverse impact on the function of the osmotic delivery device.

[0030] As shown in FIGS. 1 and 2, the osmotic delivery device 10 of oneembodiment of the present invention includes a semipermeable membrane30, which is coupled with the open end 16 of the capsule 12. Inoperation, after placing the osmotic agent within the second chamber 24of the capsule, the semipermeable membrane 30 allows liquid to pass froman environment of use into the capsule 12 to cause the osmotic agent toswell. However, the material forming the semipermeable membrane 30 islargely impermeable to the materials within the capsule 12 and to otheringredients within the environment of use.

[0031] The swelling osmotic agent exerts a pressure on the separatingmember or piston 20 and forces said separating member to move a distanceD in a direction of the arrow A. The separating member 20 applies aforce to the beneficial agent in the first chamber 22, the beneficialagent transfers the force to the valve 28. Accordingly, this forcecauses the valve 28 to move a distance C from the close position to anopen position. A clearance 34 between the valve 28 and the first end 14decreases by the distance C. In the open position, the valve 28 allowsthe beneficial agent to pass through the delivery orifice 18 to theexternal environment of use.

[0032] The osmotic agent in conjunction with the separating member 20drive the beneficial agent from the first chamber 22 and insures a flowof beneficial agent out of the delivery orifice 18. The valve 28 isretained within the delivery device 10 at the closed first end 14 of thecapsule 12 and, as described above, the valve 28 has dimensions suchthat it will not leave the delivery device 10 through the deliveryorifice 18. In a preferred embodiment, the capsule 12 has a vent 32 atthe first end 14, allowing fluid to escape from the clearance 34 betweenthe valve 28 and the capsule 12 when the valve 28 moves toward the firstend 14.

[0033] Depending on the application, the clearance 34 between the valve28 and the capsule 12 may be filled with a bio-compatible liquid or gas.The configuration of the osmotic delivery system and the material of thesemipermeable membrane 30 control the delivery rate of a beneficialagent from the osmotic delivery system.

[0034] In assembling the osmotic delivery device 10 according to theembodiment of the present invention shown in FIGS. 1 and 2, the capsule12 is prepared by forming at least one vent 32 at the first end 14 ofthe capsule. The vent 32 may be formed by mechanical drilling, laserdrilling, molding, or any other known method. The delivery port 18 is anorifice formed by conventional techniques which are known in the art.Included among these methods are mechanical drilling, laser drilling,and molding. The dimensions of the delivery port 18 in terms of bothdiameter and length will vary with the type of beneficial agent, therate at which the beneficial agent is to be delivered, and theenvironment into which it is to be delivered. The considerationsinvolved in determining the optimum dimensions of the delivery port 18for any particular capsule 12 or beneficial agent and the selection ofthe appropriate dimensions will be readily apparent to those skilled inthe art.

[0035] Once the capsule 12 of FIGS. 1 and 2 has been prepared with thevent 32 and at least one delivery port 18, having a number, shape, andsize to achieve a desired delivery rate of the beneficial agent, thevalve 28 is inserted into the capsule 12 through the open end 16.

[0036] According to one embodiment of the present invention, thebeneficial agent contained in the first chamber 22 of the capsule 12 isa flowable composition such as a liquid, suspension, or slurry, and istypically poured into the first chamber 22 of the capsule after thevalve 28 has been inserted. The separating member 20 is inserted intothe capsule 12 through the open end 16 and is positioned adjacent thebeneficial agent.

[0037] Once the osmotic agent pellet(s) or tablet(s) have been formed,they are placed inside the pre-formed capsule in the second chamber 24adjacent the separating member 20. Then the semipermeable membrane 30,according to one embodiment of the present invention, is placed into orover the open end 16 of the capsule 12 to close off and seal the openend of the osmotic delivery system.

[0038] An alternative embodiment of the invention illustrated in FIGS.3-4 includes a cap 36 having a hollow interior and a substantiallyconstant thickness cylindrical side wall 42 and an end wall 44. The cap36 forms the first end 50 of the capsule 12. In a preferred embodiment,the cap 36 affixes to the body of the capsule 12 by a snap fittingmechanism 38, such as a barbed stake. The cap 36 preferably has a vent48 in the end wall 44 which after assembly allows the valve 28 to movein a direction towards the end wall 14. In a different embodiment, thecap 36 can be pivotally rotated about a hinge in a direction of thearrow B, as depicted in FIG. 4.

[0039] The first chamber 22 of the osmotic delivery device 40 has atleast one opening 46 which communicates with the environment of use. Asshown in FIG. 3, the opening 46 is formed in the body of the capsule 12and is positioned adjacent the contacting surfaces of the cap.Alternatively, the opening 46 can be formed in the cap 36 and positionedadjacent the contacting surfaces of the body of the capsule 12. Thesemipermeable membrane 30 couples with the capsule 12 at the openedsecond end 52.

[0040] In assembling the osmotic delivery device 10 according to theembodiment of the present invention shown in FIGS. 3 and 4, the cap 36is prepared by forming at least one vent 48 at the end wall 44. The vent48 may be formed by mechanical drilling, laser drilling, molding, or anyother known method.

[0041] The capsule 12 is prepared having an opened first end 50 and anopened second end 52. The delivery port 46 is an orifice positioned atthe edge of the cap 36 adjacent the capsule 12, or the delivery port 46is positioned at the edge of the capsule 12 adjacent the cap 36. Thedelivery port 18 is formed by conventional techniques which are known inthe art. Included among these methods are laser drilling, mechanicaldrilling, grooving the edge of the capsule or cap, and molding.

[0042] The separating member 20 is inserted into the capsule 12 throughthe first or second end 50, 52. Once the osmotic agent pellet(s) ortablet(s) have been formed, they are placed inside the capsule 12 in thesecond chamber 24, adjacent the separating member 20. The semipermeablemembrane 30 is placed into or over the second end 52 to Lose off andseal that end.

[0043] Beneficial agent is added into the first chamber 22 of thecapsule 12 through the first end 50, and the valve 28 is insertedadjacent the beneficial agent in a closed position. As discussed, thevalve 28 in a closed position prevents the beneficial agent from leavingthe delivery device 10 and prevents incursion of foreign materials intothe device. Then the cap 36 is placed at the first end 50 of the capsuleto close off and seal that open end of the osmotic delivery system 10.The cap 36 may be secured to the capsule 12 by press fitting, snapfitting, threading, adhesive, welding, staking, or the like.

[0044] In general, materials suitable for use in the movable separatingmember 20 and the valve 28 are elastomeric materials includingnon-reactive polymers, as well as elastomers in general, such aspolyurethanes and polyamides, chlorinated rubbers, styrene-butadienerubbers, and chloroprene rubbers. The polymers include acrylonitrilepolymers such as acrylonitrile-butadiene-styrene terpolymer, and thelike, halogenated polymers such as polytetraflouroethylene,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and thelike.

[0045] Semipermeable compositions suitable for the semipermeablemembrane 30 are well known in the art, examples of which are disclosedin U.S. Pat. No. 4,874,388, the entire disclosure of which isincorporated herein by reference. Such possible semipermeable materialsfrom which the membrane 30 can be made include, but are not limited to,for example, Hytrel polyester elastomers (DuPont), cellulose esters,cellulose ethers, and cellulose ester-ethers, water flux enhancedethylene-vinyl acetate copolymers, semipermeable membranes made byblending a rigid polymer with water-soluble low molecular weightcompounds, and other semipermeable materials well known in the art. Theabove cellulosic polymers have a degree of substitution, D.S., on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By “degreeof substitution” or “D.S.” is meant the average number of hydroxylgroups originally present on the anhydroglucose unit comprising thecellulose polymer that are replaced by a substituting group.Representative materials include, but are not limited to, one selectedfrom the group consisting of cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di-, and tricellulose alkanylates, mono-, di-, andtricellulose aroylates, and the like. Exemplary cellulosic polymersinclude cellulose acetate having a D.S. up to 1 and an acetyl content upto 21%; cellulose acetate having a D.S. of 1 to 2 and an acetyl contentof 21% to 35%; cellulose acetate having a D.S. of 2 to 3 and an acetylcontent of 35% to 44.8%, and the like. More specific cellulosic polymersinclude cellulose propionate having a D.S. of 1.8 and a propionylcontent of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%;cellulose acetate butyrate having a D.S. of 1.8 and an acetyl content of13% to 15% and a butyryl content of 34% to 39%; cellulose acetatebutyrate having an acetyl content of 2% to 29%, a butyryl content of 17%to 53%, and a hydroxyl content of 0.5% to 4.7%; cellulose acetatebutyrate having a D.S. of 1.8, an acetyl content of 4% average weightpercent, and a butyryl content of 51%; cellulose triacylates having aD.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate,cellulose tripalmitate, cellulose trisuccinate, and cellulosetrioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such ascellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate,cellulose dipentate; coesters of cellulose such as cellulose acetatebutyrate and cellulose, cellulose acetate propionate, and the like.

[0046] Other materials for the membrane 30 are polyurethane,polyetherblockamide (PEBAX, commercially available from ELF ATOCHEM,Inc.), and injection-moldable thermoplastic polymers with somehydrophilicity such as ethylene vinyl alcohol (EVA). In general, themembrane 30 is made from semipermeable materials having a water uptakeranging from 1% to 80% but preferably less than 50%. The composition ofthe semipermeable membrane 30 is permeable to the passage of externalliquids such as water and biological liquids, and it is substantiallyimpermeable to the passage of beneficial agents, osmopolymers,osmagents, and the like.

[0047] Materials which may be used for the capsule 12 and the cap 36must be sufficiently strong to ensure that the capsule will not leak,crack, break, or distort under stresses to which it is subjected duringimplantation or under stresses due to the pressures generated duringoperation. The capsule 12 may be formed of chemically inert andbiocompatible, natural or synthetic materials which are known in theart. The capsule material is preferably a nonbioerodible material whichremains in the patient after use, such as titanium or a titanium alloy,and is largely impermeable to materials within and outside the capsule.However, the material of the capsule 12 may alternatively be abioerodible material which bioerodes in the environment after dispensingof the beneficial agent. Generally, preferred materials for the capsule12 are those acceptable for animal and human implants.

[0048] In general, typical materials of construction suitable for thecapsule 12 according to the present invention include non-reactivepolymers or biocompatible metals or alloys. Metallic materials usefulfor the capsule 12 include stainless steel, titanium, platinum,tantalum, gold, and their alloys, as well as gold-plated ferrous alloys,platinum-plated ferrous alloys, cobalt-chromium alloys and titaniumnitride coated stainless steel.

[0049] The capsule 12 may be formed from any of the wall-formingmaterials disclosed above by the use of a mold, with the materialsapplied either over the mold or inside the mold, depending on the moldconfiguration. Any of the wide variety of techniques known in thepharmaceutical industry may be used to form the capsule 12.

[0050] The osmotic agent is a liquid-attracting agent used to drive theflow of the beneficial agent. The osmotic agent may be an osmagent, anosmopolymer, or a mixture of the two. Species which fall within thecategory of osmagent, i.e., the non-volatile species which are solublein water and create the osmotic gradient driving the osmotic inflow ofwater, vary widely. Examples are well known in the art and includemagnesium sulfate, magnesium chloride, potassium sulfate, sodiumchloride, sodium sulfate, lithium sulfate, sodium phosphate, potassiumphosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate,tartaric acid, raffinose, and various monosaccharides, oligosaccharidesand polysaccharides such as sucrose, glucose, lactose, fructose, anddextran, as well as mixtures of any of these various species.

[0051] Species which fall within the category of osmopolymer arehydrophilic polymers that swell upon contact with water, and these varywidely as well. Osmopolymers may be of plant or animal origin, orsynthetic, and examples of osmopolymers are well known in the art.Examples include: poly(hydroxyalkyl methacrylates) with molecular weightof 30,000 to 5,000,000, poly(vinylpyrrolidone) with molecular weight of10,000 to 360,000, anionic and cationic hydrogels, polyelectrolytecomplexes, poly(vinyl alcohol) having low acetate residual, optionallycross linked with glyoxal, formaldehyde, or glutaraldehyde and having adegree of polymerization of 200 to 30,000, a mixture of methylcellulose, cross linked agar and carboxymethylcellulose, a mixture ofhydroxypropl methycellulose and sodium carboxymethylcellulose, polymersof N-vinyllactams, polyoxyethylene-polyoxypropylene gels,polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyuria gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross linkedindene-maleic anhydride polymers, Good-Rite polyacrylic acids havingmolecular weights of 80,000 to 200,000, Polyox Polyethylene oxidepolymers having molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps acrylate polymer polysaccharides.

[0052] The osmotic agent may be a solid osmotic tablet or a fluidosmotic agent. The osmotic tablet may be formed in many differentconceivable shapes, textures, densities, and consistencies and still bewithin the confines of the present invention. The osmotic agent may bemanufactured by a variety of techniques, many of which are known in theart. In one such technique, the osmotically active agent is prepared assolid or semi-solid formulation and pressed into pellets or tabletswhose dimensions correspond to slightly less than the internaldimensions of the respective chambers which they will occupy in thecapsule interior. Depending on the nature of the materials used, theagent and other solid ingredients which may be included may be processedprior to the formation of the pellets by such procedures as ballmilling,calendaring, stirring, or rollmilling to achieve a fine particle sizeand hence fairly uniform mixtures of each.

[0053] The present invention applies to the administration of beneficialagents in general, which include any physiologically orpharmacologically active substance. Drug agents which may be deliveredby the present invention include drugs which act on the peripheralnerves, adrenergic receptors, cholinergic receptors, the skeletalmuscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system and the centralnervous system. Suitable agents may be selected from, for example,proteins, enzymes, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,analgesics, local anesthetics, antibiotic agents, anti-inflammatorycorticosteroids, ocular drugs and synthetic analogs of these species.

[0054] Examples of drugs which may be delivered by devices according tothis invention include, but are not limited to prochlorperzineedisylate, ferrous sulfate, aminocaproic acid, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,methamphetamine hydrochloride, benzamphetamine hydrochloride,isoproterenol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperzine maleate, anisindone, diphenadione erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, dexamethasone and its derivatives such asbetamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,17-∝hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, aspirin, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mando, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, colchicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hormone, follicle stimulating hormone,chorionic gonadotropin, gonadotropin releasing hormone, bovinesomatotropin, porcine somatotropin, oxytocin, vasopressin, GRF,prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone,LHRH, LHRH agonists and antagonists, leuprolide, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, coagultionfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

[0055] On the molecular level, the various forms of the beneficial agentmay include uncharged molecules, molecular complexes, andpharmaceutically acceptable acid addition and base addition salts suchas hydrochlorides, hydrobromides, acetate, sulfate, laurylate, oleate,and salicylate. For acidic compounds, salts of metals, amines or organiccations may be used. Derivatives such as esters, ethers and amides canalso be used. A beneficial agent can be used alone or mixed with otheragents. The beneficial agent may optionally include pharmaceuticallyacceptable carriers and/or additional ingredients such as antioxidants,stabilizing agents, permeation enhances, and the like.

[0056] Animals to whom beneficial agents may be administered usingsystems of this invention include humans and other animals. Theinvention is of particular interest for application to humans andhousehold, sport, and farm animals, particularly mammals. For theadministration of beneficial agents to animals, the devices of thepresent invention may be implanted subcutaneously or intraperitoneallywherein aqueous body fluids are available to activate the osmotic agent.Devices of the invention may also be administered to the rumen ofruminant animals, in which embodiment the devices may further comprise adensity element for maintaining the device in the rumen for extendedperiods of time of up to 120 days or longer. Density elements are wellknown in the art of drug delivery devices.

[0057] The delivery devices of this invention are also useful inenvironments outside of physiological or aqueous environments. Forexample, the delivery devices may be used in intravenous systems(attached to an IV pump or bag or to an IV bottle, for example) fordelivering beneficial agents to an animal, primarily to humans. They mayalso be utilized in blood oxygenators, kidney dialysis andelectrophoresis, for example. Additionally, delivery devices of thepresent invention may be used in the biotechnology area, such as todeliver nutrients or growth regulating compounds to cell cultures. Insuch instances, activating mechanisms such as mechanical mechanisms areparticularly useful. The beneficial agent may be any of the agents whichare known to be delivered to the body of a human or an animal such asmedicaments, vitamins, nutrients, or the like. The beneficial agent mayalso be an agent which is delivered to other types of aqueousenvironments such as pools, tanks, reservoirs, and the like. Includedamong the types of agents which meet this description are biocides,sterilization agents, nutrients, vitamins, food supplements, sexsterilants, fertility inhibitors and fertility promoters.

[0058] While the invention has been described in detail with referenceto preferred embodiments thereof, it will be apparent to one skilled inthe art that various changes can be made, and equivalents employedwithout departing from the invention.

What is claimed is:
 1. An osmotic delivery device for delivery of abeneficial agent, comprising: an implantable capsule including a firstend having a beneficial agent delivery orifice and a second end; aseparating member positioned within the capsule between the first andsecond ends, the separating member dividing said capsule into abeneficial agent reservoir and a driving reservoir, said separatingmember is movable in a longitudinal direction within the capsule; anosmotic agent positioned in the driving reservoir; and a valve memberpositioned within the capsule between the first end and the beneficialagent reservoir such that the valve member opens and closes thebeneficial agent delivery orifice.
 2. The osmotic delivery device ofclaim 1, wherein said valve member is movable in a longitudinaldirection within said capsule.
 3. The osmotic delivery device of claim1, further comprising: a permeable membrane retained by the capsule andseparating the osmotic agent from a surrounding fluid, wherein inoperation, the osmotic agent imbibes the surrounding fluid through thepermeable membrane, said osmotic agent forming an osmotic solute whichexerts a pressure on the separating member and forces said separatingmember to move within the capsule, thereby moving the valve member toallow delivery of the beneficial agent through the beneficial agentdelivery orifice.
 4. The osmotic delivery device of claim 3, wherein thepermeable membrane retained by the capsule controls a rate at which thesurrounding fluid is imbibed into the osmotic agent, the rate at whichsaid surrounding fluid is imbibed into the osmotic agent controlling adelivery rate of the beneficial agent.
 5. The osmotic delivery device ofclaim 1, wherein the first end of the capsule includes a vent whichallows fluid trapped between the valve member and the first end toescape from the capsule as the valve member moves.
 6. The osmoticdelivery device of claim 1, wherein the capsule provides a clearancebetween the valve member and the first end, wherein the clearance canreceive at least a portion of said valve member in an open position. 7.The osmotic delivery device of claim 1, wherein at least a portion ofthe separating member forms a seal with an inner surface of the capsule.8. The osmotic delivery device of claim 1, wherein at least a portion ofthe valve member has a length greater than a diameter of the beneficialagent delivery orifice.
 9. The osmotic delivery device of claim 1,further comprising: a cap forming the first end of the capsule, the capcapable of receiving at least a portion of said valve member.
 10. Theosmotic delivery device of claim 9, wherein the cap is attachable to abody of the capsule with a snap fitting mechanism.
 11. The osmoticdelivery device of claim 9, wherein the cap is hingedly attached to abody of the capsule.
 12. An osmotic delivery device, comprising: animplantable capsule having first and second ends, the capsule containingan osmotic agent and a beneficial agent; a beneficial agent deliveryorifice; and a valve member positioned within an interior of the capsuleand movable from a closed position to an open position in response tofluid pressure created by the osmotic agent, in the closed position thevalve member blocks fluid flow through the beneficial agent deliveryorifice, and in the open position allows passage of fluid through thebeneficial agent delivery orifice.
 13. The osmotic delivery device ofclaim 12, further comprising: a cap forming the first end of thecapsule.
 14. The osmotic delivery device of claim 13, wherein thebeneficial agent delivery orifice is positioned adjacent the cap. 15.The osmotic delivery device of claim 12, further comprising: a movableseparating member between the osmotic agent and the beneficial agent;and a permeable membrane retained by the capsule and separating theosmotic agent from a surrounding fluid, wherein in operation, theosmotic agent imbibes the surrounding fluid through the permeablemembrane, said osmotic agent forming an osmotic solute which exerts apressure on the separating member and forces said separating member tomove within the capsule, thereby moving the valve member to allowdelivery of the beneficial agent through the beneficial agent deliveryorifice.
 16. A method of preventing contamination from entering anosmotic delivery device before activation, comprising the steps of:providing a delivery device capsule which encloses a first chambercontaining a beneficial agent, the first chamber having a beneficialagent delivery orifice communicating with an external environment, and avalve member movable within the capsule to open and close the deliveryorifice; and positioning the valve member in the delivery device capsuleat a closed position such that the valve member occludes the beneficialagent delivery orifice.
 17. The method of claim 16, further comprisingthe step of: providing an osmotic agent which imbibes a surroundingfluid into the osmotic agent to form an osmotic solute which expands andexerts a pressure on the beneficial agent and the valve member, whereinthe pressure moves the valve member from the closed position to an openposition.
 18. The method of claim 17, further comprising the step of:providing a movable separating member between the osmotic agent and thebeneficial agent such that the valve member in the opened positionallows the separating member to drive the beneficial agent from thefirst chamber, thereby insuring a flow of beneficial agent through thebeneficial agent delivery orifice and preventing contamination fromentering the delivery device.
 19. A method of controlling an initialrelease of a beneficial agent from an osmotic delivery device,comprising the steps of: providing a delivery device capsule whichencloses a first chamber containing a beneficial agent, a valve member,and a second chamber containing an osmotic agent, wherein the firstchamber has a beneficial agent delivery orifice; positioning the valvemember in the delivery device capsule at a closed position whereinbefore activation the valve member occludes the delivery orificepreventing passage of the beneficial agent contained in the firstchamber through the beneficial agent delivery orifice; imbibing asurrounding fluid into the osmotic agent to form an osmotic solute whichexpands and exerts a pressure on the beneficial agent and the valvemember, wherein the pressure moves the valve member from the closedposition to an open position whereby the beneficial agent contained inthe first chamber can pass through the beneficial agent deliveryorifice.